1,5-dihydro-2,4-benzodiazepine-3-one derivative and application thereof

Abstract

1,5-dihydro-2,4-benzodiazepine-3-one derivatives, such as a compound represented by formula I, acts on 5-HT 2A and 5-HT 2C receptors. The selectivity for 5-HT 2A is superior or similar to pimavanserin. The derivative is used for treating schizophrenia or Parkinson's disease, dementia-related behavioral disorders, and psychosis. The antipsychotic activity of the compound is equivalent to that of pimavanserin, the side effects of sedation and worsening of exercise are less than those of pimavanserin, and cardiotoxicity is less than that of pimavanserin.

The invention claimed is: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein in formula I: 
         n1 and n2 are independently integers of 1-3; 
         R 1  is selected from C1-C8 linear or branched alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, wherein the alkyl, alkenyl and alkynyl are each independently and optionally substituted with substituents selected from halogen and C1-C8 haloalkyl; 
         R 2  is selected from hydrogen, halogen and C1-C8 haloalkyl; 
         R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen, halogen, and C1-C8 haloalkyl; 
         R 7  is selected from C1-C8 linear or branched alkyl, cycloalkyl, and 
       
       
         
           
           
               
               
           
         
          wherein R 8  and R 9  are each independently selected from C1-C8 linear or branched alkyl, and the alkyl and cycloalkyl are optionally substituted with substituents selected from halogen and C1-C8 haloalkyl; 
         Z is selected from C, O and N; 
         Q and W are each independently selected from C and N; and 
         the symbol ------ represents absence of a bond or is a single bond; 
         when the symbol ------ represents the absence of a bond, the compound of formula I is a compound of formula II: 
       
       
         
           
           
               
               
           
         
         or 
         when the symbol ------ is a single bond, the compound of formula I is a compound of formula III: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of formula I according to  claim 1 , wherein, R 1  is selected from C1-C5 linear or branched alkyl, C2-C5 alkenyl, and C2-C5 alkenyl, wherein the alkyl, alkenyl and alknyl are each independently and optionally substituted with substituents selected from halogen and C1-C5 haloalkyl, or
 R 2  is selected from hydrogen, halogen, and C1-C5 haloalkyl; or   R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen, halogen, and C1-C5 haloalkyl; or   R 7  is selected from C1-C5 linear or branched alkyl, C 3 -C 10  cycloalkyl, and   
       
         
           
           
               
               
           
         
          wherein R 8  and R 9  are each independently selected from C1-C5 linear or branched alkyl, and the alkyl and cycloalkyl are optionally substituted with substituents selected from halogen and C1-C5 haloalkyl. 
       
     
     
         3 . The compound of formula I according to  claim 1 , wherein the halogen in a substitute group selected from R 1  to R 9  is independently fluorine, chlorine, bromine, or iodine. 
     
     
         4 . The compound of formula I according to  claim 2 , wherein:
 an alkyl in the C1-C5 linear or branched alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl;   the cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl.   
     
     
         5 . The compound of formula I according to  claim 1 , wherein:
 Z is O,   R 1  is C1-C5 linear or branched alkyl;   R 2  is selected from hydrogen and halogen;   R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen and halogen; and   R 7  is selected from C1-C5 linear or branched alkyl and C3-C6 cycloalkyl.   
     
     
         6 . The compound of formula I according to  claim 1 , wherein the compound of formula I is a compound of formula I-1: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C1-C5 linear or branched alkyl; 
         R 2  is selected from hydrogen and halogen; 
         R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen and halogen; 
         R 7  is selected from C1-C5 linear or branched alkyl and C3-C6 cycloalkyl; and 
         Q is N. 
       
     
     
         7 . The compound of formula I according to  claim 1 , wherein the compound of formula I is a compound of formula IV: 
       
         
           
           
               
               
           
         
         wherein: n1 and n2 are independently integers of 1-3; 
         R 1  is selected from methyl, ethyl, propyl, and butyl; 
         R 2  is selected from hydrogen, fluorine, chlorine, bromine, and iodine; 
         R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen, fluorine, and chlorine; and 
         R 7  is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, cyclobutyl, and 
       
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of formula I according to  claim 1 , wherein the compound of formula I is a compound of formula V: 
       
         
           
           
               
               
           
         
         wherein n2 is an integer of 1-2; 
         R 1  is selected from methyl, ethyl, propyl, and butyl; 
         R 3  is selected from hydrogen, fluorine, and chlorine; and 
         R 7  is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, cyclobutyl, and 
       
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of formula I according to  claim 1 , wherein the compound of formula I is a compound of formula VI: 
       
         
           
           
               
               
           
         
         wherein n1 and n2 are independently integers of 1-3; 
         R 1  is methyl; 
         R 2  is selected from fluorine and hydrogen; 
         R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen, fluorine, and chlorine; 
         R 7  is selected from isopropyl, cyclopropyl, isobutyl, methyl, and 
       
       
         
           
           
               
               
           
         
         Z is selected from C, O and N; and 
         Q and W are each independently selected from C and N. 
       
     
     
         10 . The compound of formula I according to  claim 1 , selected from the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition, comprising the compound according to  claim 1 , a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. 
     
     
         12 . A method for treating a psychiatric disease, comprising administering an effective amount of a medicament comprising the compound of  claim 1  to a subject in need thereof, wherein the psychiatric disease is schizophrenia, Parkinson's disease, behavioral symptom of dementia, or psychological symptom of dementia. 
     
     
         13 . A method for treating a psychiatric disease, comprising administering an effective amount of the pharmaceutical composition of  claim 11  to a subject in need thereof, wherein the psychiatric disease is schizophrenia, Parkinson's disease, behavioral symptom of dementia, or psychological symptom of dementia.